Glial restricted progenitor cells (GRPs) are defined by their reactivity with antibody A2B5, which recognizes a subset of c-series gangliosides (Dietrich et al., Glia 2002 40:65-77; Rao and Mayer-Proschel, Dev. Biol. 1997 188:48-63; Saito et al., J. Neurochem. 2001 78:64-74; Windrem et al., Nat. Med. 2004 10:93-97). Other antigenic characteristics of GRPs include moderate expression of the astrocytic marker glial fibrillary acidic protein (GFAP) and low expression of the neuronal markers E-CAM (polysialated N-CAM, or PSA-NCAM) and β-III tubulin (TuJ1) Dietrich et al., Glia 2002 40:65-77; Rao and Mayer-Proschel, Dev. Biol. 1997 188:48-63).
At the time the GRPs are isolated they have already differentiated endogenously beyond neural stem cells into committed lineage-restricted cells. GRPs have not been observed to induce or produce teratomas.
A very important category of neuron in the brain and spinal cord comprises those whose axons are ensheathed in myelin. When this myelin sheath is damaged, oligodendrocytes, whose living processes constitute the insulating myelin layer around neuronal axons, are destroyed. Demyelinated neurons cannot properly conduct signals and eventually will die.
When damage is incomplete, endogenous repair mechanisms are activated resulting in remyelination and partial or full return of function (Lassmann et al., Mult. Scler. 1997 3:133-136; Prineas and Connell, Ann. Neurol. 1979 5:22-31). This demonstrates the critical point that remyelination can indeed lead to restoration of function. However, the majority of patients who experience demyelination due to various diseases or trauma do not experience sufficient endogenous remyelination (Prineas et al., Ann. Neurol. 1993 33:137-151), and despite much need and effort, little progress has been made in developing products that can help restore lost function. This can be partially attributed to the multiple signals and intricate intercellular interactions that must occur to effect regeneration of the damaged myelin-producing oligodendrocytes in vivo. It is significant that cellular therapy resulting in remyelination has been demonstrated to be beneficial in animal models of demyelination.
Totoiu et al. (Exp. Neurol. 2004 187:254-265) reported benefits of local implants of murine GRPs in treating spinal cord lesions in a viral-induced murine MS model. The GRPs migrated and differentiated into oligodendrocytes, resulting in remyelination that appeared to be associated with axonal sparing. They also observed improved locomotion. Subsequent studies (Hardison et al. Exp. Neurol. 2006 197:420-429) demonstrated that the murine GRPs were able to survive and remyelinate in the presence of both inflammatory T cells and macrophages.
The shiverer mouse, which exhibits defects in production of normal myelin due to a mutation in the gene encoding myelin basic protein, is a model to study the effect of exogenous cell transplants on myelin production. Demonstration of myelin production by cellular transplants into shiverer is relevant for many demyelinating diseases, including TM and MS, as well as those of dysmyelination. Human GRPs have been shown to be capable of widespread and high-efficiency myelination of the shiverer mouse brain after perinatal xenograft (Windrem et al., Nat. Med. 2004 10:93-97). Differentiation into regionally appropriate cell types (astrocytes and oligodendrocytes) was demonstrated with no evidence of tumors. These studies were extended to show remyelination of both brain and spinal cord, which is accompanied by substantial phenotypic rescue in a subset of the implanted animals (Windrem et al., Cell Stem Cell 2008 2:553-565).